The role of calcitonin (CT) in human physiology is unknown. Pharmacologic doses of CT lower plasma calcium (Ca) and phosphate concentrations by inhibiting bone resorption, suggesting that CT might protect against excessive bone resorption and thus preserve bone mass. If so, Ct deficiency should lead to bone loss. Interest in this possibility has been piqued by the observations that women of all ages have lower plasma immunoreactive CT (iCT) values than do men; that Ca-stimulated iCT levels may decrease with age; and that estrogen therapy may raise iCT concentrations. However, the validity of existing iCT measurements on normal plasma is uncertain, and there have been no systematic studies of whether Ct deficiency, natural or surgically-induced, leads to excessive bone loss. The lack of definitive research is attributable in part to methodologic problems which are now solved. The overall hypothesis to be tested in the proposed research is that subnormal levels of CT result in increased bone resorption relative to formation, aggravating age- and sex-related bone loss. These studies are made possible by: the development here of a new technique for extraction, concentration, and assay of plasma Ct monomer (hCT-M) at concentrations as low as 0.5-1.0 pg/ml; the availability of methods for noninvasive measurement of axial and appendicular bone mass; and the presence of a modern bone histomorphometry laboratory. The extractable CT assay for the first time permits definition of subnormal plasma CT concentrations. The studies will compare levels of hCT-M, the biological active form of circulating Ct, in normal adults of both sexes and all ages, as well as in totally and partially-thyroidectomized persons and osteoporotic women. Basal and stimulated hCT-M levels will be correlated with axial and appendicular bone mass. Metabolic clearance rate determinations for hCT-M will allow the first estimates of true CT secretion rates. We will assess the effects of hCT-M deficiency on bone by histomorphometry. Finally, we will determine if estrogen therapy or high-calcium diets augment hCT-M secretion. The proposed research will provide information about the physiological role of CT in human skeletal homeostasis can never be obtained from animal or in vitro studies, and may offer valuable guidance in planning the treatment of osteoporosis.